Deregulation of gene expression is a hallmark in the development of cancer. Until recently, scientists have focused their efforts on the study of genetic alterations, such as the deletion or mutation of genes that contribute to cellular transformation. Epigenetic changes, including methylation of gene promoters and alteration of chromatin structure via histone modification, have now emerged as powerful force in controlling gene expression. Many cancers exhibit coordinated increases in DNA methylase and histone deacetylase activity. Our lab has recently uncovered a role for the histone deacetylase HDAC1 in regulating the activity of the cAMP response element binding protein (CREB). CREB is a transcription factor that has been implicated in the control of cell proliferation, cell survival, and differentiation. This proposal will explore the mechanisms of HDAC1 repression through interaction with CREB and association with methylated cAMP response elements (CREs). Methylation of the CRE has previously been proposed to inhibit expression of the tumor suppression gene BRCA1 and may play a more general role in regulating tissue-specific gene expression. The experiments outlined in this proposal will enhance our understanding of gene repression by HDAC1.